The goal of the proposed research is to identify mutations that promote susceptibility to bipolar disorder (BP); genomic mapping approaches will be used to attain this goal. Specifically, a number of established and newly developed methods will be used to pinpoint a putative BP mutation on the X chromosome, through analyses of DNA from members of three Israeli pedigrees. This locus was pinpointed to the distal long arm of X by linkage analysis; more precise localization has resulted from further genetic analyses using multiple DNA markers. The proposed studies will progressively narrow the region that could contain a BP mutation. First, markers in the region will be precisely ordered and new markers generated through construction of radiation hybrids. Next, maximal genetic localization of BP will be accomplished using several methods to detect polymorphisms at new and previously described loci. Focused studies of sub-chromosomal regions of greatest interest will be accomplished using cloning vectors capable of accommodating large inserts of human genomic DNA. A number of complementary methods will then be used to identify and characterize coding sequences from these regions. To increase the genetic power of the study, attempts will be made to identify and investigate additional families in which BP segregates in a manner consistent with X-linkage. Characterizing a BP locus on the X chromosome will enable greater understanding of the pathogenesis of BP and will likely lead to advances in diagnosis and treatment of this disorder.